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Pharmaceutical sciences
Novel Drug Delivery Systems II
Preparation of Nanoparticles
Paper No. : 08 Novel Drug Delivery Systems
Module No 15: Preparation of Nanoparticles
Paper Coordinator
Principal Investigator
Dr. Vijaya KhaderFormer Dean, Acharya N G Ranga Agricultural University
Content Writer
Prof. Farhan J Ahmad Jamia Hamdard, New Delhi
Development Team
Dr. Sushama Talegaonkar
Jamia Hamdard, New Delhi
Content Reviewer Prof A K Tiwary
Punjabi University, Patiala
.
Dr. Sushama Talegaonkar Jamia Hamdard, New Delhi
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Description of Module
Subject Name Pharmaceutical Sciences
Paper Name Novel Drug Delivery Systems II
Module Name/Title Preparation of Nanoparticles
Module Id Module 15 Quadrant I
Pre-requisites
Objectives Basic aspects of formulation development of polymeric Nanoparticles
Components of Nanoparticles
Backbone materials of polymeric Nanoparticles
Introduction and classification of formulation techniques
Emulsion evaporation methods for polymeric nanoparticles preparation
Effect of material and process variables on nanoparticles size and drug entrapment
Keywords Building block material, components, formulation technique, Solvent evaporation,
Content Reviewer
Dr. Vijaya Khader
Dr. MC Varadaraj
Prof A K Tiwarey Punjabi University, Patiala
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Formulation development
A number of techniques like self-assembly, vapor or electrostatic deposition, aggregation, nano-
manipulation, imprinting, etc. are use for the nanoparticles development where a specific protocol is
required to be followed depending on the therapeutic moieties and mode of administration. Thus,
following points must always be keep in consideration before designing any delivery systems;
immunogenicity, clinical acceptance and environmental hazards. Moreover, a basic understanding of
constituent materials like therapeutic moieties, polymers, and stabilizing is the prerequisite. These
components directly affect various attributes like size, shape, surface morphology, surface charge, drug
loading/encapsulation efficiency and drug release profile and consequently pharmacokinetics and
biodistribution thus efficacy and safety profiles as discussed in previous modules 14 “Basic
understandings of nanoparticles”.
Components of polymeric Nanoparticles: Polymeric nanoparticles comprises of followings;
1. Backbone materials (polymers)
2. Core material (drugs)
a. Hydrophilic
b. Hydrophobic
3. Stabilizer
a. Chemical cross linking agents (Glutaraldehyde, formaldehyde)
b. Emulsifying agents
Anionic surfactants: Sodium lauryl suphate, Sod. Dodocyl sulphate
Cationic surfactants: CTAB
Nonionic surfactant: PVA, Poloxamers, Span, Tween, etc.
Backbone material for polymeric nanoparticles
There are number of synthetic and natural macromolecules (polymer) which can be utilized for
the nanoparticles formulation. Non biodegradable polymers are the class which were used first time for
the development of polymeric nanoparticles however it could not gain popularity owing to the toxicity
concern. At present, different class of polymers are being used but biodegradable materials are the
polymer choice for clinical application. They superseded the existing materials due to their
biocompatibility thus lower the probability of hypersensitive reactions.
Natural biodegradable polymers
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Chitosan, alginate, gelatin, and albumin are the most common natural polymer which underwent
intensive investigation as a nanocarrier for wide variety of applications. Among them chitosan is the
most investigated. Being biodegradable and biocompatible, these macromolecules attracted scientist
community, however these biomaterials possess following limitations;
Batch to batch variation
Conditional biodegradability
Immunogenicity
Microbial load
Release profile difficult to modify
Synthetic biodegradable polymers
To overcome the limitations of natural biomaterials, synthetic biodegradable polymers came into play.
These nanoparticles have following advantages;
Minimum batch to batch variation
More stable
Release profile can be modulate by changing molecular weight
No microbial contamination
Materials properties can be manipulate according to requisite of applications
Polymers which are under intensive investigation for clinical use, some of them are in pipeline, while
few of them got FDA approval for clinical use and can be classified as shown in Table 1 (Sushama et
al., 2012).
Table 1 Classification of polymer
Origin of polymer Natural Gelatin, Albumin, Vicilin, Lactin, Legumin, Dextran,
Pullulan, Agarose, Chitosan, Alginate etc.
Synthetic PLGA, PLA, Poly-ԑ-caprolactone, polyacrylate
Degradation profile
Biodegradable PLGA, PLA, Poly-ԑ-caprolactone, polyacrylate
Non-biodegradable
Polystyrene, Eudragits, Cellulose esters, Ethyl cellulose, Cellulose acetate, Cellulose acetate propionate, Cellulose acetate butyrate
Affinity to water
Hydrophilic Gelatin, Albumin, Dextran, Pullulan, Agarose,
Chitosan, Alginate
Hydrophobic PLGA, PLA, Poly-ԑ-caprolactone, polyacrylate Polystyrene, Eudragits, Cellulose esters, Ethyl
cellulose, Poly-ԑ-caprolactone, Polylactic acid
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Mechanism/ stimuli
response Polymer
Mucoadhesive Alginate, Chitosan, Polyacrylic acid, Cyanoacrylates (commonly known as "super glues")
Photo-responsive Copolymer gels of N-isopropylacrylamide, cross-
linked hyaluronic acid
pH sensitive
Mixture of Acrylic acid and Methacryl-amidopropyl-trimethyl ammonium chloride, poly(methacrylic acid-gethylene glycol) copolymer
Temperature
sensitive
N-alkyl acrylamide homopolymers and their
copolymers
Inflammation-responsive
Cross linked hyaluronic acid.
Formulation techniques
Basically, formulation methods can be categorized into following two techniques; top–down
and bottom–up (Alexis et al., 2008). The top-down process basically deals with breakage of larges
particles into smaller one by applying energy. The major drawbacks o f this technique are time
consuming and high polydispersity index (La-Van, McGuire and Langer, 2003). In contrast, the
bottom–up techniques, involve aggregation of small or large molecules which results into larger
particles which is regulated by thermodynamic means (Keck et al., 2008). Bottom-up techniques
generates a clustered mass of particles that do not break up on reconstitution (Shrivastava, 2008).
In this section, various methods of nanoparticles preparation are classified and discussed along with
process variables, applications and limitation:
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Figure 1: Classification of formulation techniques of polymeric nanoparticles
Emulsification solvent evaporation method
It is the most ancient and widely investigated method for the preparation of
microparticles/nanoparticles from preformed polymers. Under this approach polymers are dissolved in
water immiscible organic phase organic phase (organic solvents, ethyl-acetate, dichloromethane or
chloroform) and emulsified into aqueous phase rich in stabilizers. As per the requirement, particles size
are controlled with/without the application of external energy followed by solvent evaporation under
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reduced pressure or under magnetic stirring at room temperature which results into precipitation of
preformed polymer subsequently generation of microparticles/nanoparticle suspension. The resulting
suspension is centrifuged followed washing and lyophilisation of particles pellet.
Emulsification solvent evaporation techniques can be classified into two following categories;
Single emulsion solvent evaporation
Double emulsion solvent evaporation
Single emulsion solvent evaporation
It is one of the most appropriate techniques for the encapsulation of hydrophobic drugs into
hydrophobic polymers. Under this approach drug and polymers are dissolved in common water
immiscible solvents and resulting organic phase emulsified into aqueous phase containing stabilizers.
Further, resulting coarse emulsion is sub-micronized by applying external energy though ultrasonic
devices (sonication) or high pressure homogenizer. Rest of the procedure is followed as described
above. Schematic illustration is shown in figure 2.
Merits of technique
Particles size is smaller than obtained from double emulsion methods
Drug load usually high
Demerits of techniques
Suitable only for hydrophobic drugs
Requires external energy (HPH, or sonication)
Employ some toxic solvents (dichloromethane, chloroform)
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Figure 2: Schematic representation of single emulsion solvent evaporation technique
Materials and process variables
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There are number of materials and process variables which can affects the in vitro attributes like
size, shape, zeta potential, drug loading etc. consequently in vitro and in vivo performance (Seo et al.,
2003).
1. Polymer concentration:
Polymer concentration directly affects the particles size and drug entrapment i.e. upon increasing
the polymer concentration particles size as well as drug entrapment increases. Budhian et al reported a
gradual increment in particle size up to the concentration range 5.5-66 mg/ml of PLGA while keeping
other parameters at standard conditions. It can be attributed to enhanced viscosity of organic phase
which resulting into dissipation of energy consequently might not be sufficient to break lager oil
globules into smaller nano-droplets. Similar findings were also reported by other groups also
(Desgouilles et al., 2003; Zweers et al., 2003; Song et al., 2008). Moreover, drug content into
nanoparticles was found increase as the polymer concentration was increased. The observation can also
be explained by enhanced viscosity which results into reduced diffusion of drugs. Furthermore,
enhanced particles size also results into longer diffusion path. Thus, overall it is concluded that upon
increasing polymer concentration particles size as well drug concentration increases (Budhian et al.,
2007; Song et al., 2008).
2. Molecular weight of polymer:
The effect of molecular weight can be understood by following case studies; To observe the effect
of molecular weight, molecular weight of PLGA (50:50) was varied from 7 to 63 kDa particles was
found slight increase with the molecular weight. The increment in particles size can be attributed to
enhanced viscosity of organic (Budhian et al., 2007). The findings were further validated by song et al.,
and reported similar results (Song et al., 2008).
In contrary to particles size, diverse influence of polymer molecular weight on drugs entrapment was
reported. Some researcher demonstrated enhanced drug loading with the increment of molecular
weight (Seo et al., 2008; Seo et al., 2003) while some other groups reduction in drug entrapment with
increasing molecular weight (Song et al., 2008). The discrepancies in the observations can be rectified
by followings way; reduced drug entrapment with increased MW of polymer can be attributed to
interaction between negatively carboxylic groups and positively charged X+ group of drugs. In our case
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as well as in Budhian et al. case, drug entrapment was found majorly dependent on the hydrogen
bonding between polymer and drug, since the number of free carboxylic group per gram weight of
polymer reduces upon increasing MW thus reduction in interaction between drug and polymer
consequently reduced drug entrapment, while improved drug entrapment upon increasing molecular
weight can be explained by enhanced viscosity of polymeric phase thus reduction in drug diffusion into
external aqueous phase where the hydrophobic interaction between drug and polymer was dominant
rather than hydrogen bonding.
3. Composition of polymer
To study the effect of polymer’s composition on the particles size and drug entrapment PLGA was
studied in different composition i.e. different lactic acid and glycolic ratio (L:G ratio) and di-block
polymer (mPEG-PLGA). With respect to polymer composition, different researcher reported different
findings. Insignificant increment in particles size was reported upon varying L: G ratio 50:50 to 100:0.
It can be attributed to enhanced hydrophobicity owing to hydrophobic nature of lactic acid resulting
into larger size (Budhian et al., 2007; Song et al., 2008). In contrary to particles size, drug entrapment
was found increase upon increasing lactic acid content into the polymer which was explained by
enhanced hydrophobic interaction between drug-polymer.
Effect of polymer composition was further validated by using di-block polymer (mPEG-PLGA)
comprising of PEG (MW, 2 kDa) and poly- lactic-co-glycolic acid) (PLGA; MW, 18 kDa; L/G050:50).
A large difference was observed in the NPs size of PLGA polymer (130±2) and PEG-PLGA polymer
(90±6) (Yu et al., 2012). The difference in the particles size can be attributed to difference in the
affinity to aqueous phase. PEG-PLGA polymer being more hydrophilic probably reduction in
interfacial tension between polymer and aqueous phase thus lower particles size. Similar results were
reported for pegylated lipid (Yuang et al., 2013).
4. Stabilizer type and stabilizers concentration:
Stabilizer type and their concentration have been reported to have great impact on the nanoparticles
size and drug entrapment. Jain et al. studied the effect of different stabilizers (PVA, PF68,
Didodecyldimethylammonium bromide) on the nanoparticles size and drug entrapment. They observed
highest PLGA NPs size as well as drug entrapment, ~166 nm and ~86%, respectively when PVA was
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used as a stabilizer while these value were found lowest (120 nm size and 15% entrapment) when
DMAB was exploited as a stabilizer and NPs stabilized with PF-68 left an intermediated impact on the
NPs size and drug entrapment, 130 nm size and 38%, respectively.
Lower particles size and lower drug entrapment can be attributed to differential surfactant and
micelles forming behaviour of stabilizing agents. DMAB is a cationic surfactant. Its cr itical micelles
concentration is very low and able to reduce interfacial tension more efficiently than other stabilizers
which resulting into production of nanoparticles of smaller size. This behaviour left a great impact on
drug entrapment. NPs prepared with DMAB demonstrated lowest entrapment it can be explain high
solubility of drug (Tamoxifen) into external aqueous phase owing to very low CMC of DMAB. This
effect was further validated by varying the DMAB concentration which led to the reduction in drug
entrapment upon increasing DMAB concentration. Furthermore it can be attributed to high affinity of
tamoxifen to DMAB. Another plausible reason for low entrapment can be justified by the orientation
of positively charged DMAB molecules into the polymer matrix via negatively charged carboxylic
group which resulting into blocking of hydrogen bonding between drug and polymer thus reduction in
drug entrapment. Surfactant behaviour and micelles forming properties are poorest in PVA thus
demonstrated highest entrapment as well as particles size (Jain et al., 2011).
Furthermore, effect of the stabilizer concentration on the drug entrapment and particles size was
studied. PVA is a most commonly used stabilizers for preparation of polymeric particles hence affect
of stabilizer concentration exemplified with PVA. Different group reported different observation,
Lemoine and Preat reported continuous reduction in particles size upon increasing stabilizers’
concentration. Similar observation reported by Song et al. at the concentration range 0.5-5% PVA
concentration while Zweer’s et al reported continuous increment in particles size at PVA concentration
range 5-10%. Jain et al., reported initial reduction in NPs size followed by plateaus (PVA conc. 1-3%)
while Budhian et al. reported initial size reduction followed by plateaus and subsequently increment
(0.5-10%). To resolve out the contradiction, studied concentration range need to be looked into depth.
As most of investigator, different concentration range was used. In conclusion, minimum stabilizer
concentration is required to stabilize the particles thus lowest particles size at that point, above that but
up to a certain extent it affect size insignificantly however above that range, further increasing
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stabilizer concentration leads to a increment in particles size due to dissipation of energy owing to
increased viscosity.
Similar to particles size, diverse observation has been reported with respect to drug entrapment upon
increasing stabilizer concentration. Usually, drug entrapment of hydrophobic drug was found to
decreases continuously upon increasing stabilizer concentration. It can be attributed to more leaching
of drug due to improved solubility of hydrophobic drugs in presence of high surfactant concentration
while drug entrapment of hydrophilic was reported to increase owing to enhanced viscosity of external
aqueous thus reduced diffusion where solubility is not an issue.
5. Initial drug content:
The effect of initial drug concentration on the particles and drug entrapment was studied by various
groups. Insignificant difference in particles upon increasing initial drug concentration was reported. It
can be attributed to interaction capacity of polymer with drug thus it can accommodate only a certain
amount of drug and expel out excess drug. In addition, this amount distributed into large number of
NPs thus initial drug concentration does not affect NPs size (Budhian et al., 2007; Song et al., 2008).
In contrary to particles size, initial drug concentration (Haloperido l) affected the drug entrapment.
Budhian et al reported initial increment of drug content followed by plateaus and subsequently
reduction upon continuous increasing the initial drug concentration. Initial increment in drug loading
can be explained by interaction between polymer and drug while the plateaus can be justified by its
limitation to accommodate excess molecules. Similar observations reported by Panyam et al for
dexamethasone or flutamide loaded PLGA/PLA NPs.
6. Polarity of organic solvent
Solvent polarity greatly affects the particles size and an inverse relation was observed i.e. higher
the polarity of solvent smaller the particles size. It can be attributed to reduced interfacial tension
between external aqueous phase and oily droplets due to relatively higher miscibility of polar solvent.
For examples PLGA nanoparticles prepared by using methylene chloride (DCM as solvent, low
polarity) demonstrated smaller particles size when compared with the size of nanoparticles prepared by
using ethyl acetate as organic solvent (relatively more polar). Organic solvents also affect the drug
entrapment however it dominantly depend on the affinity of drug to the solvents.
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7. Volume of organic solvent
Upon increasing the volume of organic solvent, no significant difference in particles size was
observed however continuous reduction in drug entrapment was noted (Budian et al., 2007). The
reduction in drug entrapment can be attributed to enhance solvent evaporation time thus more time
available for the partitioning of drug into organic phase and to diffuse into external aqueous phase.
8. Aqueous to organic phase ratio
Aqueous to organic phase drastically affects the particles size and drug entrapment. Different
research groups demonstrated quadratic effect on the partic les size i.e. initial reduction followed by
increment. Upon increasing w/o phase ration two competing effect do exist, interfacial tension and
shear stress. The effect of particles size and drug entrapment can be explained by dominance of two
competing effect. Initial reduction in particles size can be attributed to more efficient reduction in
interfacial tension owing to the availability of more stabilizing molecules while increment in particles
size upon further increasing aqueous phase reduction of shear stress owing to dissipation of energy
(Mainardes and Evangelista, 2005; Song et al., 2008).
Upon increasing the w/o volume ratio continuous reduction in entrapment efficiency was reported
which can be attributed to more partitioning of drug owing to continuous increment in concentration
gradient thus more diffusion of drugs.
9. Energy source and energy input
For the preparation of nanoparticles usually following two types of energy sources are used to
bring them in nano range; high pressure homogenization and sonication. The main purpose of external
energy is to reduce the particles size however it affects particles size as well as drug entrapment.
Hence, correlation between energy source and size and drug entrapment has been established below;
Budhian et al prepared haloperidol loaded PLGA Nanoparticles by using both homogenization and
sonication. They demonstrated a bimodal size distribution (larger size particles of NPs when high
pressure homogenization was used external energy source while unimodal for the particles formulated
by sonication. Jain et al also reported larger size particles with high pressure homogenizer. Thus,
sonication can be a more effective mode for size reduction. Budhian et al. reported higher drug
entrapment for the NPs developed by high pressure homogenization when compared with nanoparticles
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prepared by sonication under same set of experimental conditions thus with respect to drug entrapment
HPH is better one. Further, a diverse observation has been reported with respect to particles size upon
increasing external energy input. A continuous reduction in nanoparticles size was reported upon
increasing external energy input (sonication time or sonication power) (Mainardes and Evangelista,
2005). However, some group observed a quadratic effect on the particles size i.e. initial particles size
reduction followed increment upon increasing sonication time (song et al., 2008).
In contrary to particles size, drug entrapment usually reported to decrease upon increasing the
energy input whether through homogenization or sonication due to more leaching of drugs (Budhin et
al., 2007).
Double emulsion solvent evaporation:
As the name indicates, it is a two steps procedure, first step involves the generation of primary
emulsion (w/o) and second step is the generation of secondary emulsion (w/o/w). In the first step,
hydrophilic therapeutic moiety(s) are dissolved in the internal aqueous phase while the hydrophobic
therapeutic moiety(s) and hydrophobic polymer(s) are dissolved into the water immisc ible organic
solvent (DCM, chloroform, ethyl acetate etc.). Aqueous phase is emulsified under sonication or
homogenization over an ice bath into organic phase which may or may not contain appropriate
surfactant like span 80, pluronic F 68 etc. Resultant primary emulsion is further emulsified into
external aqueous phase containing suitable stabilizer (PVA, Pluronic F68, Tween 80 or any other). The
resultant secondary emulsion is subjected to solvent evaporation under reduced pressure or under
magnetic stirring at room temperature for appropriate time, followed by ultracentrifugation
subsequently washing and lyophilisation of obtained nanoparticles pellet. Schematic illustration is
shown in figure 3.
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Figure 3: Schematic representation of double emulsion solvent evaporation technique
Merits of technique
It is more appropriate for the encapsulation of hydrophilic moieties
Drug load usually high for hydrophilic moieties in comparison to other method
Hydrophilic and hydrophobic moieties can be encapsulated simultaneously
High polymer feed can be used
Demerits of techniques
Usually, particles size is larger than single emulsion evaporation and nanoprecipitation method
Time consuming
Requires external energy in two steps (HPH, or sonication)
Employ some toxic solvents (dichloromethane, chloroform)
Time taken and more number of materials and process variables do exit
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Materials and process variables
In this technique, number of materials and process variables involve. Most of them are similar to
single emulsion solvent evaporation and behave similarly. A few of them are unique and discussed
here.
1. Polymer concentration:
2. Molecular weight of polymer:
3. Composition of polymer
4. Stabilizer type and stabilizers concentration:
5. Initial drug content:
6. Polarity of organic solvent
7. Volume of organic solvent
8. Aqueous to organic phase ratio
9. Energy source and energy input
Here also, energy source and energy input affect the particles size and drug entrapment similarly as
discussed for single emulsion solvent evaporation. Since, this method involves the application of
external energy at two steps (at primary emulsification and secondary emulsification) hence Bilati et al.
investigated the effect of sonication process on the particles size and drug entrapment applying
sonication energy for varying duration and intensity at both the steps. Both duration and intensity of
sonication affected the particles size dominantly at the second step of mixing. They also observed a
similar effect as discussed in single emulsion solvent evaporation i.e. initial reduction followed by size
increment upon increasing the sonication time/intensity. Thus, they also recommended threshold
(sonication intensity) to control nanoparticle size.
10. Volume of internal aqueous phase
Volume of internal aqueous phase demonstrated a direct relation with particles size and drug
entrapment i.e. upon increasing volume of internal aqueous phase particles size and drug entrapment
was found to increase. Increased particles size can be attributed to reduced shear stress owing to
increased volume while higher entrapment can be justified by reduced partitioning of due to increase
volume and due to reduced shear stress.
Behave similarly as discussed
for single emulsion solvent
evaporation
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Single emulsion solvent diffusion method
Emulsion solvent diffusion methods schematically represented in the figure 4. In this method,
polymer and therapeutic moieties are dissolved into organic solvents; resultant solution is emulsified
into a small quantity of aqueous phase containing stabilizers (PVA, DMAB, SDS) under the magnetic
stirring. After emulsification, a large quantity of water is added into the emulsion consequently
solvents from the oily droplets diffuse out as a result of counter diffusion of water into the emulsion
droplets which induces the polymer precipitation consequently NPs formation. The resultant
suspension subjected to solvent evaporation followed by ultracentrifugation subsequently washing of
pallet and lyophilisation.
It differs from solvent evaporation in the following aspects; it employs partially water miscible
solvents (Phenyl methanol, propylene carbonate, ethyl acetate, isopropyl acetate, methyl acetate,
methyl ethyl ketone, butyl lactate, and isovaleric acid). Moreover, in case of emulsion evaporation,
organic solvents evaporates directly while in case of diffusion method, solvents first diffuse out
instantaneously into water then evaporates out (Moinard-Chécot et al., 2006; Quintanar-Guerrero et al.,
1998).
Merits of the techniques
It does not require external energy i.e. sonication and high pressure homogenization
Less toxic solvents are used
Demerits of techniques
Large amount of water is required to induce diffusion thus recovery of nanoparticles is difficult
Longer time is require to evaporate the solvent due more miscibility with water
Poor entrapment efficiency of drug due to high migration of drug along with polar solvent
during diffusion into aqueous phase
It cannot be applied at high polymer concentration as it does not involve external energy thus
particles size is very sensitive to polymer concentration
Materials and process variables
1. Polymer molecular weight: As discussed in single emulsion solvent evaporation
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2. Solvent polarity: As discussed in single emulsion solvent evaporation
3. Surfactant type and its concentration: As discussed in single emulsion solvent evaporation
4. Aqueous to organic phase ratio: Upon increasing aqueous to organic phase ratio, particles
size as well as drug entrapment decreases. Reduced particles size can be explained by faster
diffusion of organic solvent into aqueous phase while reduced entrapment can also attributed to
faster migration of drug molecules along with solvent.
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Figure 4: Schematic representation of Single emulsion solvent diffusion method
5. Viscosity of external aqueous phase: Viscosity of external aqueous phase also affects the
particles size as well as drug entrapment. Increasing the viscosity resulting into increased
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particles as well drug entrapment which can be attributed to reduced diffusion rate of solvent
and drug into water.
6. Polymer concentration
A direct relation between polymer concentration and particles size and drug entrapment was
observed. Upon increasing polymer concentration, particles size and drug entrapment were found
to increase which can be attributed to enhanced viscosity which imparts a high viscous resistance
resulting into reduced shear forces which hinders droplets breakdown consequently increment in
NPs size. Improved entrapment can be attributed to reduced diffusion of drug owing to enhanced
viscosity (Schchlicher et al., 1997; Budhian, Siegel and Winey, 2007; song et al., 2008).
7. Stirring speed
Emulsion homogenization speed imparted an inverse effect on the particles size and drug
entrapment. Allemann et al., demonstrated particles size reduction as well as drug entrapment
upon increasing homogenization up to 12,000 rpm. It can be attributed to high sheer stress which
results into breakdown of larger droplets into smaller while poor entrapment can be attributed to
more leaching of drugs.
8. Temperature
As discussed in previous sections, rate of solvent diffusion from oil droplets imparted a most
crucial effect on the particles size and drug entrapment. Rate of diffusion can be explained by
Stokes-Einstein equation.
According to the equation, mutual diffusion coefficient (DAB) is directly proportional to
temperature and rate of diffusion is directly related to diffusion coefficient thus upon increasing the
temperature of added aqueous phase resulting into enhance diffusion coefficient consequently
diffusion rate which lead to rapid polymer precipitation and smaller size nanoparticles.
Note: In the subsequent module (Module 16), other formulation techniques of polymeric nanoparticles
have been discussed.